The major objective of this proposal is to silence CD147 in murine Head and Neck Squamous Cell Carcinomas (HNSCC) models using small interfering RNA (siRNA) with the aim of reversing their chemoresistance and metastatic potential. HNSCC is the sixth most common cancer and the prognosis for HNSCC patients with recurrent and/or metastatic disease is very poor, with a 1-year survival rate of 20%. Approximately 60% of HNSCC patients present with advanced disease (stages III/IV) and various chemotherapy strategies do not significantly improve their overall survival, and still remain palliative. Treatment failures in HNSCC are mostly attributed to drug resistance and metastasis and currently there are no therapeutic strategies to address these two important clinical problems. Furthermore, chemotherapy agents currently being used for HNSCC treatment cause painful toxicity limiting their therapeutic application. Targeted molecular therapy with siRNA is a novel approach to overcome drug resistance in order to improve the therapeutic index and patient tolerability to chemotherapy. CD147 (Emmprin), which is overexpressed in HNSCC, mediates tumor-microenvironment cross-talk and plays a critical role in tumor invasion, metastasis, angiogenesis, chemoresistance and maintenance of cancer stem cell niche. Thus, CD147 is an ideal therapeutic target to block HNSCC metastasis and chemoresistance. Our preliminary data suggest that CD147 overexpression during HNSCC tumorigenesis is mediated by Epidermal Growth Factor Receptor (EGFR) activation and siRNA-mediated silencing of CD147 leads to concomitant decreases in the mRNA levels of MMP-9, MMP-13, Adamts 1, and tenascin-C. We hypothesize that CD147 contributes to multi-step tumorigenesis, metastasis and resistance to chemotherapy in HNSCC. To test this hypothesis, we plan to assess (1) the potential of CD147 siRNA to increase the anti-tumor therapeutic efficacy of a chemotherapy drug gemcitabine in a syngeneic orthotopic murine HNSCC model;(2) the synergistic effect of CD147 siRNA to the chemopreventive potential of EGFR-TKI against 4-NQO-induced tongue cancer in CBA mice. We propose to develop and optimize dual-ligand tagged liposomes customized for tumor selective delivery of siRNA in our animal models. This strategy involves selecting ligands that are overexpressed in tumor cells but not in normal cells. The proposed work will broaden the current understanding of the role of CD147 chemotherapy resistance and may provide new avenues to improve chemotherapeutic outcomes in HNSCC. PUBLIC HEALTH RELEVANCE: The prognosis for the patients with advanced head and neck cancer is poor and current chemoradiation therapies do not improve their progression free overall survival. We propose to develop liposomal siRNA to block CD147, a molecule implicated in resistance to chemoradiation, and test whether it enhances the efficacy of chemotherapy in a mouse model of head and neck cancer.